Richard Jackson

Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial

PURPOSE In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. PATIENTS AND METHODS Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). RESULTS The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. CONCLUSION Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.

Effect of specialist decision‐making on treatment strategies for colorectal liver metastases

One hundred and ten patients were treated with palliative chemotherapy, of whom 53 had liver‐only disease and had not been reviewed by a specialist liver surgeon. One scan was excluded as all reviewers felt it to be of insufficient quality to assess. Improved surgical technique and better chemotherapeutic manipulation of metastatic disease has increased the number of patients eligible for potentially curative resection of colorectal liver metastases. The rapid evolution in this field suggests that non‐specialist decision‐making may lead to inappropriate management. This study aimed to assess the management of colorectal liver metastases by non‐liver surgeons.

Systematic review and meta-analysis of follow-up after hepatectomy for colorectal liver metastases†

The evidence surrounding optimal follow‐up after liver resection for colorectal metastases remains unclear. A significant proportion of recurrences occur in the early postoperative period, and some groups advocate more intensive review at this time.

The unfolded protein response regulator GRP78 is a novel predictive biomarker in colorectal cancer.

Adjuvant fluoropyrimidine‐based (5‐FU) chemotherapy is a mainstay of treatment for colorectal cancer (CRC), but only provides benefit for a subset of patients. To improve stratification we examined (for the first time in CRC), whether analysis of GRP78 expression provides a predictive biomarker and performed functional studies to examine the role of GRP78 in sensitivity to 5‐FU. 396 CRC patient samples were collected in a prospective uniform manner and GRP78 expression was determined by immunohistochemistry on tissue microarrays using a well‐validated antibody. Expression was correlated with clinicopathological parameters and survival. The role of GRP78 in 5‐FU sensitivity was examined in CRC cells using siRNA, drug inhibition and flow cytometry. GRP78 expression was significantly elevated in cancer tissue (p < 0.0001), and correlated with depth of invasion (p = 0.029) and stage (p = 0.032). Increased overall 5‐year survival was associated with high GRP78 expression (p = 0.036). Patients with stage II cancers treated by surgery alone, with high GRP78 also had improved survival (71% v 50%; p = 0.032). Stage III patients with high GRP78 showed significant benefit from adjuvant chemotherapy (52% vs. 28%; p = 0.026), whereas patients with low GRP78 failed to benefit (28% vs. 32%; p = 0.805). Low GRP78 was an independent prognostic indicator of reduced overall 5‐year survival (p = 0.004; HR = 1.551; 95%CI 1.155–2.082). In vitro, inhibition of GRP78 reduces apoptosis in response to 5‐FU in p53 wild‐type cells. GRP78 expression may provide a simple additional risk stratification to inform the adjuvant treatment of CRC and future studies should combine analysis with determination of p53 status.

What Is the Best Way to Identify Malignant Transformation Within Pancreatic IPMN: A Systematic Review and Meta-Analyses

Objectives:Pancreatic intraductal papillary mucinous neoplasias (IPMNs) represent 25% of all cystic neoplasms and are precursor lesions for pancreatic ductal adenocarcinoma. This study aims to identify the best imaging modality for detecting malignant transformation in IPMN, the sensitivity and specificity of risk features on imaging, and the usefulness of tumor markers in serum and cyst fluid to predict malignancy in IPMN.Methods:Databases were searched from November 2006 to March 2014. Pooled sensitivity and specificity of diagnostic techniques/imaging features of suspected malignancy in IPMN using a hierarchical summary receiver operator characteristic (HSROC) approach were performed.Results:A total of 467 eligible studies were identified, of which 51 studies met the inclusion criteria and 37 of these were incorporated into meta-analyses. The pooled sensitivity and specificity for risk features predictive of malignancy on computed tomography/magnetic resonance imaging were 0.809 and 0.762 respectively, and on positron emission tomography were 0.968 and 0.911. Mural nodule, cyst size, and main pancreatic duct dilation found on imaging had pooled sensitivity for prediction of malignancy of 0.690, 0.682, and 0.614, respectively, and specificity of 0.798, 0.574, and 0.687. Raised serum carbohydrate antigen 19-9 (CA19-9) levels yielded sensitivity of 0.380 and specificity of 0903. Combining parameters yielded a sensitivity of 0.743 and specificity of 0.906.Conclusions:PET holds the most promise in identifying malignant transformation within an IPMN. Combining parameters increases sensitivity and specificity; the presence of mural nodule on imaging was the most sensitive whereas raised serum CA19-9 (>37 KU/l) was the most specific feature predictive of malignancy in IPMNs.

Diagnostic accuracy of individual antenatal tools for prediction of small‐for‐gestational age at birth

To determine the accuracy of fetal and newborn growth charts for the prediction of small‐for‐gestational age (SGA) at birth (birth weight < 10th centile).

Diagnostic accuracy of individual antenatal tools for the detection of the small for gestational age newborn.

To determine the accuracy of fetal and newborn growth charts for the prediction of small‐for‐gestational age (SGA) at birth (birth weight < 10th centile).

Incidence of Post- ERCP Pancreatitis from Direct Pancreatic Juice Collection in Hereditary Pancreatitis and Familial Pancreatic Cancer before and after the Introduction of Prophylactic Pancreatic Stents and Rectal Diclofenac

Objectives Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP). Methods A prospective study (1999–2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008. Results There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06–0.84) in favor of prophylaxis (0.035). Conclusions Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

OP19.10: Maternal cardiovascular changes secondary to sildenafil intake in pregnancies complicated by severe fetal growth restriction: STRIDER trial: Short oral presentation abstracts

A. Khalil1,2, A. Sharp3, C. Cornforth4, R. Jackson4, H. Mousa5, S. Stock6, J. Harrold4, M. Turner3, L. Kenny7, P. Baker8, E. Johnstone9, P. von Dadelszen10, L. Magee10, A.T. Papageorghiou11, Z. Alfirevic3 1Fetal Medicine Unit, St George’s Hospital Medical School, University of London, London, United Kingdom; 2Vascular Biology Research Centre, Molecular and Clinical Sciences Research Institute, St George’s University of London, London, United Kingdom; 3Women’s and Children’s Health, University of Liverpool, Liverpool, United Kingdom; 4University of Liverpool, Clinical Trials Unit, Liverpool, United Kingdom; 5University Department Obstetrics and Gynecology, Leicester Royal Infirmary, Leicester, United Kingdom; 6University of Edinburgh, Queen’s Medical Research Institute, Edinburgh, United Kingdom; 7University College, Irish Centre for Fetal and Neonatal Translational Research (INFANT), Cork, Republic of Ireland; 8University of Leicester, College of Life Sciences, Leicester, United Kingdom; 9Maternal and Fetal Health Research Centre, University of Manchester, Manchester, United Kingdom; 10Department of Women and Children’s Health, King’s College London, School of Life Course Sciences, London, United Kingdom; 11St George’s University of London, London, United Kingdom

Adjuvant Therapy in Pancreatic Cancer

Pancreatic cancer was once considered to be a disease without hope. Advances in regionalisation of treatment in specialist units have resulted in a great improvement in resection outcome. Studies in advanced pancreatic cancer have indicated an advantage for chemotherapy. For 15 years only the GITSG had tested adjuvant therapy in a randomised controlled trial. This small study of only 43 patients suggested a survival benefit for post-operative chemoradiotherapy combined with follow-on chemotherapy. Recently two large trials of over 800 patients, one from the EORTC and the other from ESPAC, have shown no benefit from chemoradiotherapy alone. Results from a Norwegian and from ESPAC suggest that adjuvant chemotherapy (without chemoradiotherapy) prolongs survival. The major randomisation and recruitment centres for ESPAC include Berne, Switzerland, Verona, Italy and Liverpool, UK. The ESPAC-3 Trial plans to recruit 990 patients to definitively answer the chemotherapy question as adjuvant treatment for pancreatic cancer. The new millennium brings hope at last to the most challenging cancer of all--cancer of the pancreas.